DESCRIPTION (Investigator?s abstract): Our long-term goal is to advance the understanding of epilepsy using molecular genetic systems. Epilepsy is one of the most common neurological problems known to humans; 1 percent of the population is under treatment for recurrent seizures. Antiepileptic drugs (AED) are used to treat many individuals, but they can be toxic, their side effects severe and often ineffective. If the causes of epilepsy were defined more precisely, it should be possible to devise better therapies. About one third of all epilepsies have no obvious cause, and many of these have a genetic basis. The advantage of studying genetic epilepsies is that primary defects can be pinpointed unambiguously and examined as targets for therapy. Finding these primary defects will also unravel the relationships between various physiological changes that accompany seizure. Genetic studies of human epilepsy are progressing. A handful of genes has now been mapped and identified -including several ion channels, which are familiar targets for intervention. Nevertheless, obstacles such as clinical heterogeneity and the variable or symptomatic nature of some epilepsy forms are likely to continue to limit our understanding of the genetically complex nature of primary epilepsy in humans. In addition, at the modest pace of identifying human genes, the path to new therapeutic targets through human genetics is not clear. Mouse genetic models can provide insight into molecular mechanisms of epilepsy, in the form of candidate genes and mechanisms that can be tested in humans, and several already show promise. However, until now the tools for systematically generating and efficiently screening the relevant, geneidentifiable mouse models have not been in place. The recent interest in large-scale chemical mutagenesis in mice and the inception of new screening centers provides a potential source of such models. We have therefore focused our efforts towards the use of single-gene mutants derived from a mutagenesis facility, primarily screening for mutations using a reliable seizure threshold test. We have begun to counter-screen in the presence and absence of AED to identify mouse mutants of potential clinical interest. Here we will move towards exploiting this program and proceed to discover the molecular basis of seizure susceptibility in these mutants. Our goals for the next funding period are to develop high-resolution genetic maps for new seizure threshold mutations, identify and confirm the candidate gene defective in them, evaluate the corresponding gene expression pattern at neuroanatomical resolution, and search for and map genetic modifiers of selected mutants.